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Home , Brodmann area, Brodmann area 46, Cytoarchitecture, Lunate sulcus, Prefrontal cortex, Projection fiber

cortex 48 (2012) 46e57

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Special issue: Review The : Comparative architectonic organization in the and the macaque monkey

Michael Petrides a,*, Francesco Tomaiuolo b,c, Edward H. Yeterian d,e,f and Deepak N. Pandya e,f,g a Montreal Neurological Institute, Department of Neurology and Neurosurgery, and Department of , McGill University, Montreal, QC, Canada b Auxilium Vitae Volterra, Volterra, Pisa, Italy c Department of Internal Medicine and Public Health, University of L’Aquila, Italy d Department of Psychology, Colby College, Waterville, ME, USA e Edith Nourse Rogers Memorial VA Medical Center, Bedford, MA, USA f Boston University School of Medicine, Boston, MA, USA g Beth Israel Deaconess Medical Center, Boston, MA, USA article info abstract

Article history: Detailed cytoarchitectonic studies of the human appeared during the first Received 23 February 2011 quarter of the 20th century. The incorporation of the cytoarchitectonic map by Brodmann Reviewed 18 March 2011 (1909) in the Talairach proportional stereotaxic space (Talairach and Tournoux, 1988) has Revised 7 April 2011 established the Brodmann numerical nomenclature as the basis for describing the cortical Accepted 19 July 2011 location of structural and functional findings obtained with modern . In Published online 29 July 2011 experimental anatomical and physiological investigations of the macaque monkey per- formed during the last 50 years, the numerical architectonic nomenclature used to describe Keywords: findings in the prefrontal cortex has been largely based on the map by Walker (1940). Prefrontal cortex Unfortunately, the map by Walker was not based on a comparative investigation of the cytoarchitecture of the human and macaque monkey prefrontal cortex and, as a result, the Fiber pathways nomenclature and the criteria for demarcating areas in the two species are not always consistent. These discrepancies are a major obstacle in the ability to compare experimental findings from nonhuman with results obtained in functional and structural neuroimaging of the human . The present article outlines these discrep- ancies in the classical maps and describes comparative investigations of the cytoarchi- tecture of the prefrontal cortex of the macaque monkey and human (Petrides and Pandya, 1994, 1999, 2002a) in order to resolve these discrepancies and enable easy translation of experimental research in the monkey to findings in the obtained with modern neuroimaging. ª 2011 Elsevier Srl. All rights reserved.

* Corresponding author. Montreal Neurological Institute, Department of Neurology and Neurosurgery, 3801 University Street, Montreal, Quebec, Canada H3A 2B4. E-mail address: [email protected] (M. Petrides). 0010-9452/$ e see front matter ª 2011 Elsevier Srl. All rights reserved. doi:10.1016/j.cortex.2011.07.002 cortex 48 (2012) 46e57 47

The cerebral cortex can be divided into several distinct which they were located. The stereotaxic map of Talairach cytoarchitectonic areas on the basis of differences in cell size (Talairach and Tournoux, 1988) was adopted by the functional and type and in the arrangement of the in the various neuroimaging community to provide a standard proportional cortical layers, such as differences in cell density, the pres- stereotaxic space within which all brains could be trans- ence or absence of certain layers, and the relative thickness of formed in order to correct, partially, for differences in size and the layers. The first complete cytoarchitectonic maps to be shape and permit reporting of the structural or functional published were those of Campbell (1905), who divided the neuroimaging findings in a common stereotaxic space (see human cerebral cortex into a few general regions, and the Brett et al., 2002). Gradually, the Talairach stereotaxic space, map of the monkey (Cercopithecus) cerebral cortex published which was based on one brain, evolved into the Montreal by Brodmann (1905). A little later, Brodmann (1908, 1909, 1914) Neurological Institute (MNI) standard proportional stereotaxic published his famous map of the human cerebral cortex. In space (MNI space) that was based on several brains (Collins Brodmann’s maps, several cortical areas were identified and et al., 1994). The Talairach space and its modern develop- labeled with distinct numbers (Figs. 1A and 2A). In 1925, ment, the MNI space, constitute now the common stereotaxic Economo and Koskinas published a major atlas of the human framework within which specific activity changes in func- cerebral cortex in which the different architectonic areas were tional neuroimaging studies and/or morphological changes in labeled with letters (Fig. 1B) and provided a detailed descrip- the brain as a result of training or disease are described. The tion of the different areas and excellent photomicrographs. In use of the Brodmann (1909) cytoarchitectonic numbers to the 1950s, the maps of Bailey and Bonin (1951) and Sarkissov describe the different areas of the cerebral cortex in the et al. (1955) appeared, the latter map being a modified Talairach and Tournoux (1988) atlas also meant the wide version of the Brodmann map based on the examination of adoption of the Brodmann cortical scheme by the functional several brains. Various maps focused on the cytoarchitecture neuroimaging community in the description of functional and of the human , such as the map by Sanides (1962), morphological changes in the human cerebral cortex. the map of the orbital frontal region by Beck (1949), the The identification of the cytoarchitectonic area within dorsolateral frontal areas 9 and 46 by Rajkowska and which the functional activity occurred is a complex issue that Goldman-Rakic (1995), Broca’s region by Amunts et al. (1999), requires careful consideration of many factors. Probability and areas 10 and 13 by Semendeferi et al. (1998, 2001). Apart maps which provide quantitative information about the from the cytoarchitectonic studies mentioned above, some location of particular structures in the Talairach or MNI space investigators described the architecture of the cerebral cortex have been published to aid the investigator in making deci- based on (Vogt, 1910; Vogt and Vogt, 1919) or pigment sions about the locus of the activation. These probability maps architecture (Braak, 1979). have been of particular cytoarchitectonic areas (e.g., Amunts Architectonic studies of the human cerebral cortex were of et al., 1999) or morphological structures, such as the pars relatively limited interest until the emergence of modern opercularis (e.g., Tomaiuolo et al., 1999) or the orbitofrontal functional neuroimaging in the 1980s. The demonstration sulci (e.g., Chiavaras et al., 2001). In the latter case, the with positron emission tomography (PET), initially, and a little assumption has been that architecture maintains a more-or- later with functional magnetic resonance imaging (fMRI) that less stable relation to certain morphological entities, which focal changes in cortical activity could be detected in relation is known to be the case for some structures. For instance, the to various aspects of motor and cognitive performance primary visual area (the striate cortex) is known to lie within required a stereotaxic map to describe the location of these the banks of the calcarine , the primary changes and to identify the cytoarchitectonic areas within (area 4) always lies in the anterior bank of the

Fig. 1 e The frontal cortex of the human brain as parcellated in the cytoarchitectonic maps of (A) Brodmann (1909) and (B) Economo and Koskinas (1925). 48 cortex 48 (2012) 46e57

Fig. 2 e Cytoarchitectonic map of the monkey cerebral cortex by (A) Brodmann (1905) and the prefrontal cortex by (B) Walker (1940). and the primary somatosensory cortical area 3 always lies in since the overall activity changes demonstrated by neuro- the posterior bank of the central sulcus. When such relations imaging within a region do not provide any information about are known, a reasonable inference can be made of the archi- the actual neuronal computations that underlie particular tectonic location of certain functional changes. Nowadays, functional contributions, examination of the physiological and cortical activation foci can be detected even in individual pharmacological properties of neurons recorded in these areas subjects and, therefore, the functional activations can be in alert behaving animals are necessary. related easily to particular sulci/gyri in an individual subject Since the 1950s, the development of experimental (e.g., Amiez et al., 2006). anatomical methods to study the connections between The frontal cortex, which is the focus of the present article, different brain areas, such as the silver degeneration (Fink and comprises several architectonic areas in both the human and Heimer, 1967; Nauta, 1957), initially, and later the anterograde the monkey brain (e.g., Barbas and Pandya, 1989; Brodmann, tracer methods (e.g., autoradiography, Cowan et al., 1972), 1905, 1908, 1909, 1914; Economo and Koskinas, 1925; Petrides made it possible to identify axonal fiber tracts in experimental and Pandya, 1999, 2002a; Sarkissov et al., 1955; Walker, 1940). animals. In such material, one can identify the precise course Experimental anatomical studies in the monkey have shown and termination of commissural and association cortico- that the afferent and efferent connections of these areas are cortical axonal pathways, as well as the cortico-subcortical quite distinct (for review of cortico-cortical connections, see projection leading to structures such as the , Yeterian et al., 2011, and for the pathways used, see Petrides , pons, , tectum, and . and Pandya, 2002b). Afferent connections provide a particular These anterograde axonal tracing methods can be supple- frontal area with information about perceptual and mented with retrograde tracer techniques, using horseradish processing occurring in specific cortical and subcortical areas, peroxidase (Mesulam, 1978) or fluorescent dyes (Keizer et al., while efferent connections provide the means by which 1983; Kuypers et al., 1980), which provide detailed informa- a particular frontal cortical area can control information pro- tion not only about the precise cortical area within which cessed in other cortical and subcortical areas. Neuroimaging specific pathways originate, but also the precise neurons in studies in the human brain can provide some evidence about particular cortical layers that give rise to the axonal connec- the functional contribution of these areas by demonstrating tions. This experimental methodology gave rise to the golden overall increases in activity within particular regions (indi- era of experimental during which detailed rectly estimated via the blood oxygenation level) in relation to information about the connections of the different cortical various aspects of cognitive processing (i.e., the so-called areas of the primate cerebral cortex was gathered based on “activations”). However, studies in the monkey are necessary studies on various nonhuman primate species, in particular to link unambiguously particular functional contributions to the macaque monkey. specific architectonic areas by means of analysis of the During the last 10 years, major developments in imaging cognitive effects of lesions restricted to these areas. In addition, have permitted the reconstruction and visualization of cortex 48 (2012) 46e57 49

pathways in the human brain using diffusion MRI (e.g., Catani (including their origin) from those that terminate in area 44 et al., 2005; Frey et al., 2008; Makris et al., 2005, 2007; Mori and (and their origin)? Since information is lost in voxels with Zhang, 2006; Saur et al., 2008; see Jones, 2008, for review of the convergence of axons (distinct fiber bundles that come close methodology). Diffusion MRI has provided an important new together) and divergence of axons (some fibers leave while tool to explore the connections of the human brain and is others remain), it will be difficult to estimate these two fiber already beginning to play an important role in clinical prac- bundles with accuracy. Thus, DTI can reconstruct the major tice, such as in the evaluation of potential impairments in stem of the superior longitudinal fasciculus bringing infor- pathways in abnormalities of the nervous mation from inferior parietal areas to the ventral frontal region system (see, Johansen-Berg and Behrens, 2006). Although (e.g., Catani et al., 2005; Frey et al., 2008; Makris et al., 2005; undoubtedly diffusion MRI is a major development in the Thiebaut de Schotten et al., 2012, this issue), but cannot esti- study of the white matter pathways and their abnormalities in mate with accuracy which fibers terminate in rostroventral the human brain, one must be aware of the limitations of this area 6 and which ones terminate in ventrolateral prefrontal method. Diffusion MR imaging permits the delineation of the areas 44 or 45. This precise differentiation can be achieved with stems of the major white matter association pathways that anterograde tracer studies in the macaque monkey because link various cortical regions together and the projection fiber labeled axons can be seen to emerge from the cortical area that pathways that connect cortical regions with subcortical was injected and can be traced all the way to their synaptic nuclei. However, present limitations of the method do not terminations in another distant cortical area (for an example, permit the delineation of the precise origins within particular see Petrides and Pandya, 2009). cortical areas of axonal pathways and the precise termina- The above considerations indicate that, although the stems tions of axons within specific architectonic cortical areas (for of the major pathways can be visualized with DTI in the an excellent discussion of limitations even with 9.4 T scan- human brain, detailed information about the precise cortical ning to resolve the details of the optic chiasm, see Roebroeck origins of axons and their precise cortical terminations must et al., 2008). The limitations of diffusion imaging for tractog- be derived from anterograde and retrograde tracer studies in raphy are the result of partial volume averaging in single the macaque monkey. In the companion article in the present voxels of complex fiber relations, such as the crossing of issue by Yeterian et al. (2011), we review the cortico-cortical fibers, close juxtaposition of distinct fiber tracts (“kissing”), connectivity of the various prefrontal architectonic areas as and the presence of sharp curves. Other current limitations of shown in experimental anatomical studies in the macaque diffusion MRI for tractography stem from the models used to monkey. However, the success of such an endeavor to inform estimate fiber orientations, such as the classical tensor model issues of connectivity in the human brain will be critically which has problems when there are two or more fiber orien- dependent on the extent to which architectonic areas have tations (Catani and Stuss 2012, this issue; Catani et al., in been defined by the same criteria in the monkey and the press). The distance from seed to target and how tortuous human frontal cortex. Cytoarchitectonic studies of the cortex a pathway may be also affect the reliability of tractographic of the monkey appeared at about the same time as those of the results (for an overview of the method, see Johansen-Berg and human cortex, but unfortunately the numerical designations Behrens, 2006, and Jones, 2008). employed did not always refer to areas with comparable As an example, suppose that a group of axons originate in architectonic features and location (see Petrides and Pandya, cytoarchitectonic area PF of the rostral inferior 1994, 1999, 2002a, for detailed discussion of this problem). and another group originate from the immediately and For instance, Brodmann published a map of the cortex of the caudally adjacent area PFG and these axons run in close monkey in 1905 (Fig. 2A), but the numerical designations he proximity to each other in the superior longitudinal fasciculus used were not consistent with those used in his map of the in the white matter of the . Diffusion human brain that was published later in 1908 and 1909 tensor imaging (DTI) can reconstruct the overall major stem of (Fig. 1A). He did not identify area 46 in the monkey and used the superior longitudinal fasciculus but cannot distinguish the the number 12 for the frontopolar region in contrast to his group that originated from PF as opposed to the axon map of the human brain where the frontopolar region was group that originated from PFG since these distinct axon identified with the number 10 (compare Fig. 1A with Fig. 2A). groups will be running in close juxtaposition (“kissing”) and Furthermore, the number 10 was used by Brodmann to iden- giving essentially the same diffusion profile. Similarly, tify a part of the ventrolateral frontal region in the monkey. although the stem of the major pathways can be recon- These are only some of the discrepancies in the two maps. structed, there are limitations in correctly deriving the pres- Brodmann expressed considerable uncertainty about his ence or absence of the terminations of the axons within subdivisions of the frontal cortex and expressly stated, in his particular cortical areas. Let us continue with the example famous monograph of 1909, that the numbers he used do not above of the two groups of axons one of which originated from always denote homologous areas in different species. area PF of the inferior parietal lobule and the other from area The discrepancies in architectonic delineations and the PFG that is just caudal to the first one. Both these axon groups uncertainty expressed by Brodmann about his demarcation of run in close proximity as part of the superior longitudinal frontal cortical areas led to abandonment of his monkey map. fasciculus and one of them is directed to rostroventral pre- In 1940, Walker published a map of the cytoarchitecture of the motor area 6, while the other is directed to area 44. Since both frontal cortex of the macaque monkey (Fig. 2B) and attempted these axonal groups will be running in close proximity and to use, as far as possible, the numerical nomenclature used by both will enter the white matter of the ventral precentral , Brodmann in the human brain. For instance, he designated the can DTI resolve those that terminate in premotor area 6 frontopolar cortex of the monkey as area 10 (as was the case in 50 cortex 48 (2012) 46e57

the map of the human brain by Brodmann) and identified an cytoarchitectonic and topographical criteria so that a mean- area 46 and an area 45 that were missing from Brodmann’s ingful crosstalk between experimental anatomical, physio- map of the monkey frontal cortex. Walker’s map became the logical and lesion-behavior research on monkeys and basis of subsequent cytoarchitectonic investigations of the functional and structural neuroimaging in the human brain macaque monkey frontal cortex. The Walker scheme, with could proceed. This comparative examination yielded a par- some modifications introduced by Barbas and Pandya (1989) cellation of the prefrontal cortex that is comparable in the two and Preuss and Goldman-Rakic (1991), provided the basis for species (Fig. 3), thus resolving the major problems that had the description of the results of anatomical connectional arisen from discrepant parcellations in the classic maps. studies on macaque monkeys with various anterograde and There is no doubt that the basic architectonic plan is the retrograde tracers during the golden era of experimental same in these two primate species. It is often claimed that the neuroanatomy. Similarly, the location of recording and prefrontal cortex has undergone disproportionate expansion microstimulation sites in physiological studies and the place- in the human brain (Passingham, 1973; Schoenemann et al., ment of lesions in behavioral investigations of the frontal 2005), but this claim has been challenged more recently. cortex in the monkey were often guided by Walker’s map. Semendeferi et al. (2002) have used MRI to examine the size of But there was a major problem. Although Walker (1940) the frontal cortex in several primates and report that the harmonized the designations of some of the areas of the relative size of the human frontal cortex is that expected for monkey prefrontal cortex with those used by Brodmann in his a primate of the human size. Furthermore, their results map of the human brain, he did not compare the cytoarchi- demonstrated that the human frontal cortex is not dispro- tecture of the human and the macaque monkey frontal lobe. portionately large relative to that of the great , although it Thus, several issues arise. Walker identified a large region is larger in comparison with that of the lesser apes and within the banks of the sulcus principalis and the cortex monkeys. In addition, Smaers et al. (2011) provided evidence immediately surrounding it as area 46, but he left open the that neither the white matter nor the gray matter of the frontal question whether all of it or part of it corresponded to area 46 lobe is disproportionately expanded in the human brain. They as identified by Brodmann in the human brain. Walker suggest, instead, that there might have been a left prefrontal introduced an area 45 along the inferior branch of the arcuate specialization in relative white to gray matter volume and sulcus, but, since he had not compared its architecture with that may be the extreme case in this evolutionary that in the human brain, he repeatedly pointed out that he trend. Thus, greater connectivity of the left prefrontal cortex was not certain whether it corresponded to Brodmann’s area (and hemisphere) and, perhaps, Broca’s region, may have been 45 in the human brain. Furthermore, Walker introduced terms a factor in language evolution, rather than the appearance of that were discrepant with those used by Brodmann in the new architectonic areas (Thiebaut de Schotten et al., 2012, this human brain. He labeled the most ventral part of the macaque issue). The left prefrontal specialization suggested by the data ventrolateral prefrontal region, where it continues into the discussed above is of interest in relation to evidence from orbital frontal cortex, as area 12 and used the term area 13 for intrinsic functional connectivity by Liu et al. (2009) that the caudal orbitofrontal region. These numbers are discrepant asymmetry of the human brain is controlled by various factors, with those of Brodmann who, in the human brain, used the one of which appears to be a left-lateralized factor that number 47 to identify a part of the ventrolateral prefrontal includes certain prefrontal and temporal areas related to region as well as most of the caudal orbital frontal region, semantic processing. At present, only for frontopolar area 10 is while acknowledging that this huge region is architectonically there some evidence that it may be larger in the human brain heterogeneous. than in apes (Semendeferi et al. 2001). The above discrepancies are a serious problem for modern In the present article, we shall not provide an exhaustive because they impede the ability to compare description of the architectonic features of the various areas experimental findings from nonhuman primates with results since this can be found in our primary research reports obtained in functional and structural neuroimaging of the (Petrides and Pandya, 1994, 1999, 2002a). We shall instead human brain. As pointed out above, although advances in guide the reader through the problems that were raised by the structural neuroimaging (e.g., DTI) permit reconstruction of discrepancies in the classic maps and their resolution. In this the major pathways of the human brain, these reconstruc- manner, the reader will appreciate the changes made to the tions cannot reveal the precise origins and terminations of the classic maps and will be provided with a key to the companion axonal connections (as can be done in the experimental tracer article by Yeterian et al. (2011) which describes the connec- studies in the monkey). Although attempts are sometimes tions in the macaque monkey in the context of the Petrides made to infer these terminations in the human brain with and Pandya comparative map of the frontal cortex. probabilistic DTI tractography (e.g., Behrens et al., 2007)or functional connectivity analysis (e.g., Margulies et al., 2009; van den Heuvel et al., 2009), these must be interpreted with 1. Architectonic correspondence issues in caution and in the context of the experimentally studied the dorsolateral frontal cortex of the macaque pathways in the macaque monkey (Berlucchi 2012, this issue). monkey and the human brain: the problem of In the 1990s, we began a strictly comparative re- areas 9, 46, and 9/46 examination of the architecture of the macaque monkey and the human frontal cortex (Petrides and Pandya, 1994, 1999, In the macaque monkey, Walker (1940) labeled the highly 2002a). The aim of this research was to define the various granular cortex within and around the sulcus principalis as prefrontal areas in the two species using the same area 46. In the posterior end of the sulcus principalis, area 46 is cortex 48 (2012) 46e57 51

Fig. 3 e Cytoarchitectonic maps of the lateral, medial, and orbital surfaces of the frontal lobe of the human (A) and the macaque monkey (B) brains as parcellated by Petrides and Pandya (1994). In B, the inset diagram displays the region within the lower limb of the arcuate sulcus to show the cytoarchitectonic areas lying within its banks.

replaced by area 8 and in the rostralmost end by area 10 (see between area 46 and area 8 on the of the Fig. 2B). This definition of area 46 in the macaque monkey has human brain, is comparable to the cortex in the posterior half dominated the anatomical and physiological literature in the of the principal sulcus of the monkey that Walker labeled as description of cortical connections and interpretation of the area 46. Although this portion of the cortex on the middle location of physiological recordings and excisions to examine frontal gyrus that Brodmann labeled as area 9 shares with area structure-to-function relations. However, Walker (1940) and 46 a well developed layer IV, it can be distinguished from area many investigators (e.g., Barbas and Pandya, 1989; Preuss and 46 by the presence of large, deeply stained pyramidal neurons Goldman-Rakic, 1991), subsequently, acknowledged that this in the lower part of layer III which are found in area 9 of the large region labeled as area 46 is not homogeneous in its middle frontal gyrus but not in area 46. Area 46 has a layer III cellular structure. Which one of the different parts of Walker’s that contains small to medium pyramidal neurons giving it area 46 in the monkey is homologous to Brodmann’s area 46 in a rather uniform appearance. the human brain? In our comparative examination of the architecture of the In the human brain, area 46 of Brodmann (equivalent to human and the monkey frontal cortex, we noted that only the area FDD of Economo and Koskinas) is separated from area 8 anterior part of Walker’s area 46 in the monkey exhibits the on the middle frontal gyrus by area 9, but in Walker’s monkey characteristics of area 46 on the human middle frontal gyrus. map it is not (compare Fig. 1A with Fig. 2B). Furthermore, We have therefore restricted the designation area 46 only to Brodmann identifies area 9 also on the this cortical region of the monkey (area marked in yellow in above area 46 (see Fig. 1A). In our comparative architectonic Fig. 3). The cortex on the lips of the caudal portion of the investigation, we noted that area 9 on the principalis, which Walker also included in his area 46 gyrus of the human brain has a poor layer IV (similar to the (see Fig. 2B) but which has features characteristic of that part poor layer IV that one encounters in Walker’s area 9 in the of area 9 that lies on the middle frontal gyrus of the human monkey), but area 9 on the middle frontal gyrus has a well brain, we have labeled as area 9/46 in both species (area developed layer IV and, in this respect, it is more similar to marked in dark green in Fig. 3). Although the connectivity of area 46 than to area 9 on the superior frontal gyrus. Further- these subdivisions shares certain features, there are also more, the very granular cortical area 9, which is interspersed striking differences, especially regarding connections with the 52 cortex 48 (2012) 46e57

inferior parietal cortex. For instance, the caudal and ventral Is there an area in the macaque monkey frontal cortex that parts of the sulcus principalis (area 9/46v) have major - exhibits the characteristics of area 45 of the human brain and is tomotor inputs that are not shared by area 9/46d or area 46 this area in the monkey the same as “area 45” of Walker? Note proper (see Petrides and Pandya, 1999, 2002a, 2009; reviewed that Walker’s area 45 was not defined as a result of compar- in Yeterian et al., 2011, in this issue). ative architectonic examination. (3) Is there a cortical area in the ventrolateral frontal region of the monkey cortex that exhibits the characteristics of the part of Brodmann’s area 47 2. Architectonic correspondence issues in that occupies the ventrolateral frontal region of the human the ventrolateral frontal cortex of the macaque brain? Note that Brodmann’s area 47 in the human brain monkey and the human brain: the problem of occupies the most ventral part of ventrolateral frontal cortex areas 44, 45 and 47 and extends to most of the caudal orbital frontal region and that Brodmann (1909) explicitly stated that it is a heteroge- Major discrepancies exist between the classical cytoarchitec- neous region that could be further subdivided. tonic maps of the human ventrolateral frontal cortex and The cortex occupying the pars opercularis of the human those of the macaque monkey. In the map of the human brain brain and labeled as area 44 by Brodmann (Fig. 1A) and area by Brodmann (Fig. 1A), the ventral part of the FCBm by Economo and Koskinas (Fig. 1B) is a dysgranular is occupied by areas 4 and 6. In front of premotor area 6, on the frontal region that exhibits a narrow and interrupted layer IV, , three areas are identified: area 44 on the and large pyramidal neurons in the lower part of layer III and in pars opercularis, area 45 on the pars triangularis, and part of layer V. This dysgranular region emerges just in front of pre- area 47 on the pars orbitalis of the inferior frontal gyrus. The motor area 6. Because the inferior branch of the arcuate sulcus presence of the agranular motor (area 4) and premotor (area 6) is more-or-less vertically oriented and its architecture severely cortical regions in the ventral part of the precentral gyrus of distorted in standard coronal sections, we examined several the monkey and the human cortex has not been the subject of monkey brains in which the inferior branch of the arcuate much debate (compare Figs. 1A and 2A). By contrast, the sulcus was sectioned perpendicular to the direction of the identification of areas 44, 45 and 47 has been controversial. sulcus, i.e., in a direction optimal for architectonic analysis. Brodmann (1905) did not identify these areas on the ventro- The results showed that, anterior to ventral area 6 and buried lateral frontal cortex of the monkey (Fig. 2A) and Walker (1940) mostly in the most ventral part of the posterior bank and in the labeled a small strip of the cortex along the inferior branch of fundus of the inferior branch of the arcuate sulcus, there is the arcuate sulcus as “area 45” (Fig. 2B) and the remainder of a dysgranular cortical area that exhibits the characteristics of the inferior frontal region as “area 12” and more dorsally as area 44 of the human brain (Fig. 3B inset; see Petrides and part of area 46. However, Walker only tentatively suggested Pandya, 2002a, 2009; Petrides et al., 2005). Immediately rostral that the strip of cortex that he labeled as “area 45” in the to this area, starting in the anterior bank of the inferior branch monkey (Fig. 2B) may correspond to the cortical area 45 in the of the arcuate sulcus, there is another cortical area that human brain as labeled by Brodmann (Fig. 1A) because he had exhibits the characteristics of area 45 of the human brain not carried out a comparative examination of the monkey and (Fig. 3B). Brodmann’s area 45 (or area FDG according to the the human ventrolateral frontal cortex (see Walker, 1940,p. nomenclature of Economo and Koskinas) is a typical lateral 67). The issue of the definition of area 45 in the human and the prefrontal area exhibiting a very well developed layer IV (in macaque monkey brains was further complicated in the 1990s sharp contrast to dysgranular area 44). In addition, there is when some physiologists adopted the term “area 45” to refer a characteristic of area 45 that sets it apart from other lateral to the ventral part of the frontal eye field in the macaque prefrontal areas: it is populated by clusters of unusually large monkey. This is the part of the frontal eye field from which and deeply stained pyramidal neurons in the deepest part of small amplitude can be evoked with electrical layer III (Amunts et al., 1999; Economo and Koskinas, 1925; microstimulation, in contrast to the more dorsal part of the Petrides and Pandya, 1994, 2002a). These were the character- frontal eye field, referred to as area 8, where large amplitude istics that we observed in the macaque monkey cortex starting saccades are evoked (e.g., Schall et al., 1995). This usage approximately in the anterior bank of the ventral part of the emerged because, in Walker’s map, area 45 is shown to start inferior arcuate sulcus and continuing on the ventrolateral just below area 8A in the dorsal part of the inferior branch of frontal cortex for a considerable distance up to a small dimple the arcuate sulcus (Fig. 2B). However, area 45 as shown by that we labeled the infraprincipal dimple (Fig. 3B). Note that Walker extends all the way to the ventralmost tip of the this area as defined by Petrides and Pandya (1999, 2002a) using inferior branch of the arcuate sulcus (Fig. 2B) from where the criteria of area 45 of the human brain is not coincidental oculomotor responses have never been evoked. In addition, with that labeled as area 45 by Walker (1940); although it area 45 of the human brain has never been linked to oculo- includes part of Walker’s area 45 (compare Fig. 3B with Fig. 2B). motor function, but rather to verbal and non-verbal retrieval Because the term area 45 has also been used in physio- from long-term memory (e.g., Petrides et al., 1995; Petrides, logical studies in the monkey to refer to the most ventral part 1996). Thus, in our comparative examination of the architec- of the frontal eye field which lies on the dorsal part of the ture of the ventrolateral frontal region of the macaque and the inferior branch of the arcuate sulcus close to area 8A (e.g., human frontal cortex (Petrides and Pandya, 1994, 2002a), we Schall et al., 1995), we carried out a study to examine whether had to address the following questions: (1) Is there an area 44 electrical microstimulation along the part of the inferior in the ventrolateral frontal cortex of the macaque monkey arcuate sulcus defined as area 45 by the criteria of the human that lies immediately in front of agranular premotor area 6? (2) brain resulted in oculomotor responses (Petrides et al., 2005). cortex 48 (2012) 46e57 53

The results showed that oculomotor responses could only be and architectonically heterogeneous zone that not only obtained from the more dorsal part of the inferior branch of included the ventralmost part of the ventrolateral frontal the arcuate sulcus, the part which does not exhibit the char- region, but also extended on the caudal orbital surface as far as acteristics of human area 45. Thus, we concluded that both the medial (see Fig. 1A). The designation “area the large and the small amplitude parts of the frontal 47” has not been used in any of the maps of the monkey brain, eye field of the monkey lie at the interface of area 6 with area 8 but Walker (1940) labeled a large part of the ventrolateral and do not include area 45 if the latter is defined by the criteria frontal region as “area 12” (see Fig. 2B). Medial to area 12 on the used to identify area 45 in the human brain (Petrides et al., orbital frontal region, Walker labeled the cortex as “area 13”, 2005). Furthermore, we were able to show that neuronal caudally, and “area 11”, rostrally. Our comparative architec- activity in macaque area 45 when defined by the criteria of the tonic analysis of the ventrolateral and orbital region in the human brain is involved with active retrieval as is the case macaque monkey and the human brain established that with human area 45 (see Cadoret and Petrides, 2007). This Walker’s area 12 corresponds to only a part of conclusion is consistent with everything known about areas 47, namely the part that covers the ventralmost portion of the 44 and 45 of the human brain, which have never been linked to ventrolateral frontal region and extends as far as the lateral oculomotor function and instead have been linked to orbital sulcus. We therefore labeled this part of Brodmann’s controlled memory retrieval (see Petrides, 1996). area 47 as “area 47/12” to acknowledge the architectonic Finally, we addressed the question of the part of the correspondence between these cortical regions in the two macaque monkey ventrolateral frontal region that corre- primate brains (Fig. 3). The part of Brodmann’s area 47 that sponds to the ventrolateral part of Brodmann’s area 47 in the extends further medially onto the caudal orbital region corre- human brain. Here we should emphasize that the designation sponds to area 13 of Walker in the monkey (Mackey and “area 47” was used by Brodmann (1909) to refer to a very large Petrides, 2009; Petrides and Pandya, 1994, 2002a).

Fig. 4 e The dorsal (superior longitudinal fasciculus and arcuate fasciculus) and the ventral (extreme capsule fasciculus) pathways linking perisylvian parietal and temporal cortical regions with the homologues of Broca’s region in the macaque monkey brain. The dorsal pathway (in red) is the superior longitudinal fasciculus (SLF) which originates from cortical areas of the inferior parietal lobule and terminates in areas 44, 45B, and 45A of Broca’s region. Fibers originating from the caudal part of the arch around the caudal end of the lateral fissure forming the arcuate fasciculus (AF) and blend with the fibers of the superior longitudinal fasciculus in the white matter of the inferior parietal lobule. The ventral (area 6), which controls the orofacial musculature, receives its strongest input from the most rostral part of the inferior parietal lobule (area PF) via a part of the superior longitudinal fasciculus (in green). The ventral pathway (in yellow) is the extreme capsule fasciculus (ECF) which originates from cortical areas of the intermediate and anterior superior temporal region, courses through the extreme capsule, and terminates primarily in area 45. Abbreviations: AF, arcuate fasciculus; AS, arcuate sulcus; CS, central sulcus; ECF, extreme capsule fasciculus; IOS, inferior occipital sulcus; IPD, infraprincipal dimple; IPS, ; LS, ; PS, sulcus principalis; SLF, superior longitudinal fasciculus; STS, superior temporal sulcus. 54 cortex 48 (2012) 46e57

Areas 44 and 45 in the left hemisphere of the human brain are inputs, the homologs of Broca’s region receive input from the considered to constitute the anterior language region, often mid-lateral temporal region via the extreme capsule (Fig. 4). The known as Broca’s region (Amunts et al., 1999; Petrides and extreme capsule fasciculus was first demonstrated by Petrides Pandya, 2002a). Besides the theoretical importance for and Pandya (1988) but, in the earlier study, we had not language evolution of the demonstration of areas 44 and 45 in described the ventrolateral frontal inputs as terminating in the ventrolateral frontal cortex of the macaque monkey, this areas 44 or 45 since these areas had not been defined at the time. research opened up the possibility of examining in detail the In our re-examination of these inputs in 2009, it was clear that axonal pathways that bring input into the macaque areas that most of the axons coursing through the extreme capsule from are homologs of Broca’s region. We therefore re-examined the the temporal region terminated in area 45, with a minor parietal and temporal inputs of these newly defined ventrolat- contingent terminating in area 44. None of these connections eral frontal cortical areas using the autoradiographic technique terminated in premotor area 6 (Petrides and Pandya, 2009). The which permits the precise delineation of not only the course of parietal inputs to Broca’s region via the superior longitudinal the axons but also their precise termination (Petrides and fasciculus may correspond to the contingent arising from Pandya, 2009). The results indicated two independent streams Geschwind’s region as described by Catani et al. (2005) (Bizzi of connections that bring information from parietal and et al., 2012). The specificity of the connections of the different temporal cortex to the homologs of Broca’s region. The rostral- post-Rolandic cortical areas suggests that it would be better, most inferior parietal lobule area PF projects via the third branch when possible, to refer to specific cortical areas rather than of the superior longitudinal fasciculus to the ventral part of the general regions, such as posterior parietal or temporo-parietal premotor cortex. By contrast, most of the parietal input to areas junction when referring to cortico-cortical connectivity and 44 and 45 arises from areas PFG and PG, with a gradation such function. that area PFG projects strongly to area 44 and area PG projects We have recently used functional connectivity analyses of more strongly to area 45. These parietal inputs are conveyed via resting state fMRI data, which detect coherent low-frequency the superior longitudinal fasciculus and there is a smaller input fluctuations in the BOLD signal, in order to examine predic- from the caudalmost temporal region via the arcuate fasciculus tions about the connections of Broca’s region in the human (Fig. 4). In addition to these parietal and posterior temporal brain based on the macaque monkey data (Kelly et al., 2010). In

Fig. 5 e Schematic diagram integrating functional connectivity results between ventral area 6, area 44 and area 45 with perisylvian inferior parietal and temporal cortical regions (Kelly et al., 2010) with information concerning white matter tracts that join these regions as studied in the macaque monkey (Petrides and Pandya, 2009). Abbreviations: AF, arcuate fasciculus; Ang, ; aSMG, anterior ; CS, central sulcus; ECF, extreme capsule fasciculus; IFS, ; IPS, intraparietal sulcus; MTG, ; pSMG, posterior supramarginal gyrus; SLF, superior longitudinal fasciculus; STG, ; STS, superior temporal sulcus. cortex 48 (2012) 46e57 55

this study with normal human subjects, we used two methods and diffusion MRI, must be interpreted with caution and in the to test hypotheses concerning differential connectivity of context of hypotheses derived from data obtained with ventral area 6, area 44 and area 45 based on the anatomical experimental tracing methods in the monkey. tracing study (Petrides and Pandya, 2009) that established the connectivity of homologous regions in the macaque monkey: (1) manual selection of seed regions-of-interest within Acknowledgments ventrolateral frontal cortex, on the basis of local sulcal and gyral , and (2) data-driven partitioning of ventrolat- The research was supported by NSERC Grant RGPIN 7466. eral frontal cortex into regions exhibiting distinct connectivity patterns, using a spectral clustering algorithm. 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